To date, all trials of lung cancer chemoprevention agents performed in the United States and Europe have failed to show that this therapy confers a benefit to individuals at increased risk of developing lung cancer. Most of these trials examined the chemopreventive efficacy of retinoid-based regimens. Through studies performed under our current SPORE grant, which evaluated mechanisms of retinoid response and resistance in human bronchial epithelial (HBE) cells, we showed that retinoids suppress the proliferation of HBE cells by inhibiting the activity of mitogen-activated protein (MAP) kinase pathways and that retinoids do not inhibit MAP kinase pathways in non-small cell lung cancer (NSCLC) cells, which are resistant to the growth inhibitory effects of these agents. These findings indicated that activation of specific kinase pathways is crucial to maintaining the proliferation and survival of normal and neoplastic HBE cells. Based on this novel observation, we began to explore the activity of other kinase pathways in normal and neoplastic lung tissues. We have evidence that the phosphatidylinositol 3-kinase (PI3K) pathway is activated in bronchial premalignancy and NSCLC. Further, inhibition of the PI3K pathway inhibits the growth of NSCLC cells. The biologic effects of PI3K pathway inhibitors on NSCLC cells varied depending on the specific components of the cell that were inhibited; inhibition of either PI3K or cJun N-terminal kinase (JNK), which is activated by PI3K through RAC-1, induced proliferative arrest, whereas combined inhibition of PI3K and JNK induced apoptosis. We hypothesize that because activation of the PI3K pathway is crucial for transformation of HBE cells to bronchial premalignancy and subsequently for survival of NSCLC cells, targeting the PI3K pathway will be effective in preventing lung cancer and treating clinically evident disease. The goal of our SPORE competitive renewal is to develop lung cancer chemopreventive and treatment approaches that target the PI3K pathway and induce apoptosis of bronchial premalignancy and lung cancer cells. We propose to investigate the efficacy of inhibitors of the PI3K- and JNK-dependent pathways that are currently in various stages of preclinical and clinical development in lung cancer prevention and therapy using multiple complementary preclinical models, including an in vitro lung carcinogenesis model (Aim 1) and three animal models of human lung cancer (Aim 2). We will investigate the importance of inhibiting the PI3K pathway in the chemopreventive actions of ZD1839, an inhibitor of the ErbB1 tyrosine kinase, in a clinical trial targeting individuals at high lung cancer risk (Aim 3). We will translate findings from these studies into the clinic by developing a clinical trial to investigate the lung cancer chemopreventive or therapeutic efficacy of the novel PI3K pathway inhibitors investigated in Aims 1 and 2.